SMAD4 and cancer: The Smad4 proteins, which have an important impact on the occurrence, development, and metastasis of malignant tumors,348 are vital downstream effectors of the TGF-β signaling pathway.349 TGF-β ligands bind to membrane receptors to form two types of receptor heterodimers, type I and II, which can activate downstream Smad2 and Smad3 proteins and then combine with Smad4 to form a transcription complex in the nucleus, thereby regulating the transcription of target genes and exerting inhibitory effects on cell growth.340,350